Greater Than Ninety Percent of Patients with Acute Leukemia and Hyperleukocytosis Who Receive Leukocytapheresis Treatment Successfully Undergo Induction Chemotherapy: Follow-up Analysis of Data from 2006-2013 JC Hofmann, MD 1,2 ; KM Grant, MD 3 ; DD Kiprov, MD 1,2 1 Apheresis Care Group, 2 Division of Immunotherapy, 3 Division of Hematology, Department of Medicine, California Pacific Medical Center, San Francisco, California 1
Disclosure of Conflicts of Interest Greater Than Ninety Percent of Patients with Acute Leukemia and Hyperleukocytosis Who Receive Leukocytapheresis Treatment Successfully Undergo Induction Chemotherapy Jan Hofmann, MD has reported the following financial relationships with commercial interests related to the content of this educational activity: Consulting Fees: Fresenius Medical Care 2
Hematologic Diseases (ASFA 2013 Categories) Disease Category Rec. Grade Primary, idiopathic TTP I 1A Thrombotic microangiopathy (TMA): - Ticlopidine I 1B - Clopidogrel III 2B - Cyclosporine/Tacrolimus III 2C - Gemcitabine IV 2C - HSCT-associated (refractory) III 1B Hyperviscosity (monoclonal gammopathies) I 1B Catastrophic Antiphospholipid Syndrome (CAPS) II 2C Hyperleukocytosis: - Leukostasis (WBC depletion) I 1B - Prophylaxis (AML; ALL, if WBC>400K) III 2C Sickle cell disease: - acute CVA (RBCX) I 1C - acute chest syndrome (RBCX) II 1C Malaria (severe falciparum malaria; RBCX) II 2B 3
Acute Leukemia (with hyperleukocytosis): Hyperleukocytosis: Circulating WBC or leukemic blast cell count >100 X 10 9 /L (>100K) Acute Myelogenous Leukemia (AML): very large, stiff myeloblasts Acute Lymphoblastic Leukemia (ALL): lg., deformable lymphoblasts Leukostasis (clinical presentation): hyperviscosity, microvascular leukoaggregates, tissue ischemia, infarction/thrombosis, hemorrhage: CNS symptoms (confusion, somnolence, delirium, coma, hemorrhage) Pulmonary complications (dyspnea, hypoxemia, respiratory failure, diffuse alveolar hemorrhage, pulmonary infiltrates). AML myeloblasts ( endothelial adhesion molecule expression) AML (WBC >100K; occas. >50K); ALL (WBC >400K) 4
Acute Leukemia: treatment options Treatment: Definitive induction chemotherapy; hydroxyurea Management of tumor lysis syndrome: intravenous fluid, allopurinol or rasburicase, electrolyte replacement, alkalinization of urine, dialysis. Avoid RBC transfusions ( cell mass); FFP, platelet transfusions PRN Leukocytapheresis: Treatment of leukocytosis/leukostasis ( surgical debulking ) May metabolic sequellae of tumor cell lysis syndrome ASFA Cat. I (leukostasis); ASFA Cat. III (prophylaxis) Indication for leukocytapheresis: - Clinical evidence of leukostasis; blast crisis; hyperleukocytosis - Blast crisis: blast cells >75% or blast cell count >100K 5
Acute Leukemia: Suggested Leukocytapheresis Goals Daily leukocytapheresis until patient reaches WBC goal (before initiation of definitive chemotherapy): usually 1-3 treatments: ASFA recommendations: treatment goals: - AML: asymptomatic pts: WBC <100K symptomatic pts: WBC <50K & no leukostasis sxs - ALL: asymptomatic pts: WBC <400K symptomatic pts: WBC <400K & no leukostasis sxs 6
Acute Leukemias: AML Acute Myelogenous Leukemia: WBC ~100-300K: pts present with leukostasis (CNS &/or resp.) sxs Myeloblasts: very large, stiff, non-deformable, tend to adhere to each other causing WBC thrombi at lower WBC counts. WBC 45-60% per treatment Usually 1-3 leukapheresis txs to reach WBC goal Recommend post-tx CBC (assess immediate WBC): - rarely rebound in WBC: minimal to no splenomegaly 7
Acute Leukemias: ALL Acute Lymphoblastic Leukemia: WBC ~250-550K: pts present with leukostasis (CNS &/or resp.) sxs Lymphoblasts: large, deformable, tend to adhere less to each other, only causing WBC thrombi at higher WBC counts. WBC 35-45% per treatment Usually 1-4 leukapheresis txs to reach WBC goal Recommend post-tx CBC (assess immediate WBC): - often notable rebound in WBC because of moderate splenomegaly 8
WBC Leukocytapheresis (WBC sequestration & rebound) 1000K Leukocytapheresis Leukocytapheresis 560K 500K Chemo Time 0 470K 380K Platelets PRBC 22:00 01:30 11:00 14:00 12 y.o. pt with ALL: WBC 780K (60% blasts), resp. distress, confusion, spleen 5 cm RCM. S. Torloni, Mayo Clinic, Scottsdale, AZ 9
WBC Depletion in Acute Leukemia: Evidence from the literature (1) Safety & effectiveness of leukocytapheresis in AML & ALL (~18 case series, cohort studies, or controlled trials); no RCTs: Bug et al (2007): retrospective, cohort study (53 pts with AML): - 25 pts: chemotherapy (Ch) vs. 28 pts: Ch + leukapheresis (Lp) - risk of early death (21 days): Ch + Lp group (16%) vs. Ch group (32%) - median survival similar: Ch + Lp group (7.5 mos.); Ch group (6.5 mos.) Giles et al (2001): retrospective, cohort study (146 pts with AML): - 75 pts (Ch alone) vs. 71 pts (Ch + Lp) - risk of early death (14 days): Ch + Lp group (13%) vs. Ch group (23%) - median CR similar: Ch + Lp group (62%) vs. Ch group (59%) 10
WBC Depletion in Acute Leukemia: Evidence from the literature (2) Chang et al (2007): retrospective, cohort study (75 pts with AML): - 37 pts (Ch) vs. 38 pts (Ch + Lp [22] or cranial irrad. [10] or both [6]) - risk of death (30 d): Ch/Lp/CI group (40%) vs. Ch group (27%) - mean survival: Ch/Lp/CI group (10.6 mos.) vs. Ch group (34.8 mos.) - WBC>200K: Ch/Lp/CI group (34%) vs. Ch group (16%) - 2 sxs of leukostasis: Ch/Lp/CI group (32%) vs. Ch group (16%) Thiebaut et al (2000): retrospective, case series (53 pts with AML): - 53 pts (Lp +/- Ch); median # txs = 1 (1-4 txs); early death (7 days): 3.8% - low level of early death 96% (51/53) pts received induction chemo. 11
WBC Depletion in Acute Leukemia: Evidence from the literature (3) Summary: Leukapheresis appears to decrease short-term mortality rate; does not increase overall survival. Pts selected for leukapheresis treatment are often sicker and have a higher underlying mortality rate. Leukapheresis appears to be helpful to survive blast crisis and start induction chemotherapy. Bruserud O et al. Transfus Med 2013; 23 (6): 397-406. Hofmann JC et al. Blood 2011; 118 (21): abstr 4281. Bug G et al. Transfusion 2007; 47: 1843-1850. Lowe EJ et al. Pediatr Blood Cancer 2005; 45: 10-15. Chang MC et al. Am J Hematol 2007; 82 (11): 976-980. Porcu P et al. Ther Apher 2002; 6: 15-23. Blum W, Porcu P. Semin Thromb Hemost 2007; 33 (4): 350-54. Giles FJ et al. Leuk Lymphoma 2001; 42: 67-73. Novotny JR et al. Eur J Haematol 2005; 74: 501-510. Thiebaut A et al. Ann Hematol 2000; 79: 501-506. 12
AML & ALL patients (1/06-9/13) 1/06-9/13: 3,164 patients (pts); 24,708 apheresis treatments (txs) Acute leukemia (AML or ALL): 231 pts (7.3%); 593 txs (2.4%) - AML: 143 pts (4.5%); 320 leukocytapheresis txs - ALL: 88 pts (2.8%); 273 leukocytapheresis txs Retrospective, case series: - Blast crisis: blast cells >75% or blast cell count >100K - Leukostasis symptoms (sxs): CNS and/or pulmonary manifestations - Goals: AML pts: WBC <55K & resolution of leukostasis sxs ALL pts: WBC <80-100K & resolution of leukostasis sxs - Outcomes scale: improved; stabilized; unchanged - Improved: attain WBC goal & resolution of leukostasis sxs - Stabilized: attain >50% reduction in WBC & resolution of sxs - Unchanged: attain neither WBC level; no resolution of sxs 13
AML patients (ACG database: 1/06-9/13) AML (143 pts; 320 txs): Median initial WBC: 213K (range 66-427K); final WBC: 53K (17-137K) Median # txs: 2 (mean 2.2 txs/pt; range 1-5 txs); WBC 45-60% per tx Median age: 52 years old (y.o.) (6-85 y.o.); <20 y.o. (13%) Blast crisis: 89%; Leukostasis sxs: 0 sxs (11%), 1 sx (53%), 2 sxs (36%) Outcome: Improved (73%); stabilized (25%); unchanged (2%) Received induction chemotherapy: 91% pts Expired pts: 12 pts (8.4%) expired w/i 1-4 days after completing txs: - blast crisis (83%); 2 sxs leukostasis (75%); prior ICH or CVA (42%) - ventilated/hypotensive (100%); unable to tolerate chemotherapy (92%) Non-treated pts: 17 additional pts: - 11 pts: stabilized/received induction chemotherapy - 6 pts: too unstable to treat (all expired within 24 hours) 14
ALL patients (ACG database: 1/06-9/13) ALL (88 pts; 273 txs): Median initial WBC: 341 (range 104-764K); final WBC: 77K (30-297K) Median # txs: 2 (mean 3.1 txs/pt, range 1-7 txs); WBC 35-45% per tx Median age: 19 years old (y.o.) (3-80 y.o.); <20 y.o. (36%) Blast crisis: 84%; Leukostasis sxs: 0 sxs (21%), 1 sx (65%), 2 sxs (14%) Outcome: Improved (61%); stabilized (36%); unchanged (3%) Received induction chemotherapy: 97% pts Expired pts: 2 pt (2.3%) expired w/i 1 day after completing treatments: + blast crisis, 2 sxs leukostasis, prior ICH, ventilated/hypotensive + unable to tolerate chemotherapy Non-treated pts: 4 additional pts: - 3 pts: stabilized/received induction chemotherapy - 1 pt: too unstable to treat (expired within 24 hours) 15
Study Limitations Retrospective, case series (not cohort or prospective study) Lack of long-term outcome data Some ALL patients may have been overtreated 16
Summary: Hyperleukocytosis, leukostasis, and WBC depletion Carefully selected patients with acute leukemia (and evidence of impending thrombosis) appear to benefit significantly from WBC depletion. A limited number of treatments (median 2 treatments) can enable a high percentage of patients to receive induction chemotherapy, improves short-term clinical outcomes, and is critical to allow patients to proceed to definitive treatment. A randomized controlled trial to assess efficacy of leukocytapheresis treatment in this subset of patients (specifically patients with ALL) should be considered. 17
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Summary: WBC Depletion in Acute Leukemia: Evidence from the literature (3) Leukapheresis appears to decrease short-term mortality rate; does not increase overall survival. Pts selected for leukapheresis treatment are often sicker and have a higher underlying mortality rate. Leukapheresis appears to be helpful to survive blast crisis and start induction chemotherapy. Given the relatively few clinical trials in ALL (studying the utility of leukapheresis), a RCT should potentially be considered. Bruserud O et al. Transfus Med 2013; 23 (6): 397-406. Hofmann JC et al. Blood 2011; 118 (21): abstr 4281. Bug G et al. Transfusion 2007; 47: 1843-1850. Lowe EJ et al. Pediatr Blood Cancer 2005; 45: 10-15. Chang MC et al. Am J Hematol 2007; 82 (11): 976-980. Porcu P et al. Ther Apher 2002; 6: 15-23. Blum W, Porcu P. Semin Thromb Hemost 2007; 33 (4): 350-54. Giles FJ et al. Leuk Lymphoma 2001; 42: 67-73. Novotny JR et al. Eur J Haematol 2005; 74: 501-510. Thiebaut A et al. Ann Hematol 2000; 79: 501-506. 20